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Cost-Effectiveness of Combined GnRHa and rhGH Therapy versus Monotherapy in Girls with Central Precocious Puberty Based on a Markov Model Integrating Real-World and Pooled Published Cohort Data

This study utilizes a Markov model integrating real-world and pooled cohort data to demonstrate that while adding recombinant human growth hormone to GnRHa therapy for central precocious puberty may be cost-effective for lighter children with significant height deficits under a Chinese healthcare-payer perspective, the conclusion remains sensitive to body weight, treatment duration, and the substantial quality-of-life burden associated with daily injections.

Original authors: Wei Song

Published 2026-07-25

📖 5 min read🧠 Deep dive

CC BY 4.0

Original authors: Wei Song

Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). ✨ This is an AI-generated explanation of the paper below. It is not written or endorsed by the authors. For technical accuracy, refer to the original paper. Read full disclaimer

Imagine a world where your body's internal clock is set to "fast forward." For some children, puberty starts way too early, like a movie playing at double speed before the story is even halfway through. This condition, called Central Precocious Puberty (CPP), causes kids to shoot up in height quickly at first, but their bones mature just as fast, closing the door on future growth prematurely. It's like a plant that blooms too soon and stops growing before it can reach its full potential.

To fix this, doctors usually use a "pause button" medicine called a GnRHa. It stops the puberty clock, giving the child more time to grow naturally. But sometimes, even with the pause button, the child doesn't grow as tall as their genes promised. So, doctors have a second tool: a daily growth hormone shot (rhGH) that acts like a turbo-boost, trying to squeeze out extra height. The big question isn't just "does it work?" but "is it worth the massive price tag and the daily needle?" This paper is a financial detective story, trying to figure out if that turbo-boost is a smart investment for families and the healthcare system, or if it's just an expensive gamble.

The Great Height Heist: A Cost-Benefit Adventure

Think of growing up as a race to a finish line called "Final Adult Height." In the world of Central Precocious Puberty, the finish line moves closer every day because the body ages too fast. The standard strategy is to hit the brakes with a medicine called GnRHa. But for some runners, hitting the brakes slows them down too much, and they still won't make it to the finish line they were destined for.

Enter the "Turbo-Boost": adding a daily growth hormone shot (rhGH) to the mix. This paper asks a very practical question: Is paying for this turbo-boost worth it? The authors built a digital simulation—a "Markov model"—which is basically a giant, complex video game that plays out thousands of scenarios of a girl's growth journey from diagnosis to adulthood. They fed this game real-world data from their own hospital and combined it with results from four other big studies involving 132 girls.

The Verdict: It Depends on the Weight and the Clock

The simulation found that adding the growth hormone does indeed help. On average, girls who got the combo treatment gained an extra 0.44 points on their "height score" (a specific measurement called bone-age-corrected height SDS) compared to those who just got the pause-button medicine. That sounds like a win, right? But here comes the catch: the cost.

For a typical 30-kilogram child treated for three years, the standard medicine costs about ¥49,104. The combo treatment? It jumps to ¥164,496. That's an extra ¥115,392 just for the extra growth. When the authors crunched the numbers to see if that extra height was worth the extra cash, they calculated a "cost-effectiveness ratio." In their base scenario, the combo therapy came in just under the line of what is considered a "good deal" in China (which is set at three times the country's per-person income, or about ¥300,000 per unit of height gained).

The "But..." Factor: Uncertainty and Burden

However, the paper doesn't shout "Buy it for everyone!" Instead, it sounds a very cautious alarm. When the researchers ran their simulation 10,000 times to account for real-life messiness, the combo therapy was only a "good deal" about 68.7% of the time. That means in roughly one out of every three scenarios, it was actually too expensive for the height gained.

The simulation showed that the deal falls apart quickly if two things change:

The child is heavier: If the child weighs more than 35 kg, the cost of the daily hormone shots (which are priced by weight) skyrockets, making the treatment too expensive for the results.
The treatment lasts too long: If the therapy goes on for more than 3 years, the bill piles up, and the value drops below the "good deal" threshold.

There's also a hidden cost that money can't buy: the "injection burden." The authors created a playful but serious "burden score" to measure how annoying the treatment is. While the standard medicine requires a few clinic visits every few months, the combo therapy requires a daily needle stick. In their scoring system, the combo therapy deducted 48 extra "happiness points" every three months just for the daily shots and extra blood tests. This daily grind is a real stress for kids and parents, a factor that pure math often forgets.

The Final Takeaway

So, what's the bottom line? The paper suggests that the combo therapy might be a smart financial move, but only for specific players in the game. It works best for lighter children (under 35 kg) who need treatment for a shorter time (around 3 years) and have a big gap between their current height and their genetic potential. For heavier kids or those needing long-term treatment, the cost likely outweighs the benefit.

The authors argue against a "one-size-fits-all" approach. Instead of automatically giving every child the turbo-boost, doctors and families should look at the specific numbers: How much does the child weigh? How much height are they missing? And can the family handle the daily needle routine? It's not a guaranteed win, but for the right child, it could be the difference between a short story and a long, tall one.

Technical Summary: Cost-Effectiveness of Combined GnRHa and rhGH Therapy in Girls with Central Precocious Puberty

Problem Statement
Central Precocious Puberty (CPP) is a common pediatric endocrine disorder characterized by premature activation of the hypothalamic-pituitary-gonadal axis, leading to accelerated bone-age advancement and compromised final adult height. While Gonadotropin-releasing hormone agonist (GnRHa) monotherapy is the standard of care, it often results in residual height deficits relative to genetic target height due to the dampening of the growth hormone–IGF-1 axis. Consequently, clinicians increasingly consider adding recombinant human growth hormone (rhGH) to GnRHa therapy to improve height outcomes. However, this combination therapy introduces substantial increases in direct medical costs and a significant daily injection burden. There is a lack of formal health-economic evidence from a Chinese healthcare-payer perspective evaluating whether the incremental clinical benefit of adding rhGH justifies its high cost.

Methodology
The study employed a Markov decision-analytic model to compare GnRHa monotherapy against GnRHa+rhGH combination therapy from a healthcare-system perspective.

Model Structure: The model simulated a 6-month cycle from diagnosis to the attainment of final adult height. Health states were defined by bone-age response, treatment adherence, and final height attainment relative to genetic targets.
Data Integration:
- Effectiveness: The primary effectiveness outcome was the change in bone-age-corrected height standard deviation score ( $\Delta$ BAHSDS). The effect-size input was derived from a pooled analysis of four published cohorts (Pasquino 1999, Mul 2005, Proos 2010, Liang 2015; $N=132$ ) reporting completed final-height outcomes. A local real-world cohort ( $N=18$ ) treated at the authors' center (2019–2023) provided supportive interim data and was used to characterize baseline characteristics, costs, and quality-of-life burdens, but was not pooled into the final effect-size estimate to avoid conflating interim and final outcomes.
- Costs: Direct medical costs included drug acquisition (GnRHa and rhGH) and monitoring (bone-age radiographs, hormonal assays, IGF-1 safety monitoring). Costs were based on local Chinese pricing.
- Quality of Life: An investigator-constructed scoring framework quantified treatment-burden decrements (e.g., daily injections, clinic visits), acknowledging that this instrument was hypothesis-generating and not externally validated against standard pediatric QoL tools.
Analysis: The Incremental Cost-Effectiveness Ratio (ICER) was calculated against a Willingness-to-Pay (WTP) threshold of three times China's 2023 per-capita GDP (approx. ¥300,000 per unit $\Delta$ BAHSDS). Sensitivity analyses included one-way variations for body weight, treatment duration, effect size, and drug price, as well as a probabilistic sensitivity analysis (PSA) using 10,000 Monte Carlo iterations.

Key Results

Clinical Efficacy: The pooled literature indicated a mean difference in $\Delta$ BAHSDS of 0.44 (95% CI 0.30–0.58) favoring combination therapy. The local cohort's interim data showed a numerically consistent difference (0.44).
Cost Analysis: For a base-case 30-kg child treated for 3 years, the total direct cost was ¥49,104 for monotherapy and ¥164,496 for combination therapy. The incremental cost was ¥115,392, driven almost entirely by rhGH acquisition.
Base-Case ICER: The base-case ICER was ¥262,255 per unit $\Delta$ BAHSDS gained, falling below the ¥300,000 WTP threshold.
Sensitivity and Uncertainty:
- Probabilistic Sensitivity Analysis (PSA): Despite the favorable base-case ICER, the PSA revealed only a 68.7% probability that combination therapy was cost-effective at the ¥300,000 threshold.
- Thresholds: The ICER exceeded the WTP threshold if body weight surpassed approximately 35 kg or treatment duration exceeded 3 years.
- Adherence: An illustrative analysis suggested that if real-world adherence to daily rhGH injections drops to 70–85% (compared to trial-level 100%), the effective benefit diminishes, and the ICER rises above the threshold.
Treatment Burden: The combination therapy incurred a substantially higher quality-of-life decrement (48 points per 3-month cycle) compared to monotherapy, primarily due to daily subcutaneous injections.

Significance and Claims
The authors claim that GnRHa+rhGH combination therapy is plausibly, but not unconditionally, cost-effective for girls with CPP. The study concludes that the value of combination therapy is highly sensitive to patient-specific factors:

Patient Selection: The strategy is most cost-effective in lighter children (lower body weight) with a larger predicted height deficit relative to genetic target height, where the growth window is longer.
Adherence: The economic case relies heavily on high adherence to daily injections; without structured adherence support, the cost-effectiveness may be eroded in routine practice.
Policy Implications: Since GnRHa costs are common to both arms, policy efforts to improve affordability should target rhGH pricing rather than GnRHa pricing.

The paper emphasizes that combination therapy should not be applied uniformly as a default upgrade for all CPP patients. Instead, treatment selection should be individualized based on height deficit, family affordability, and the capacity to manage the injection burden. The authors note that their findings are limited by the small size of the local real-world cohort, the use of sample-size weighting rather than formal random-effects meta-analysis for the pooled data, and the use of a non-validated QoL scoring framework. They call for larger prospective cohorts and validated quality-of-life instrumentation to strengthen the evidence base for these clinical and economic decisions.

Technical Summary: Cost-Effectiveness of Combined GnRHa and rhGH Therapy in Girls with Central Precocious Puberty

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